In this Project, we propose to continue the investigation of potentially modifiable nutritional and hormonal risk factors for incident and fatal breast cancer, including those that affect survival after the diagnosis of breast cancer. This work will use the stored blood and urine samples, archived DNA, repeated questionnaires, and long follow-up in the Nurses'Health Study (1976- 2012 with approximately 10,000 incident invasive breast cancers). Exposures will also be related to tumor characteristics using pathology blocks from incident breast cancers. We will specifically examine the relation of vitamin D and melatonin to breast cancer risk, intakes and blood levels of 1-carbon nutrients to risk of breast cancers characterized by global hypomethylation (assessed by LINE-1 methylation), and change in alcohol consumption to breast cancer incidence. We will also assess risk factors in relation to tumors classified by expression of multiple receptors and in relation to fatal breast cancer. The association of modifiable factors to risk of breast cancer will be examined among women at elevated genetic risk defined by ongoing GWAS's. LINE-1 methylation of breast cancers will be evaluated as an independent prognostic factor, and the possibility that low physical activity and greater weight reduce survival through the insulin signaling pathway will be examined. Post diagnostic dietary insulin index and protein quality will be evaluated as predictors of survival. This Project shares common biological and mechanistic themes with Projects 2, and 3, including the role of vitamin D, 1-carbon metabolism, and energy balance in relation to cancer incidence and survival, and like the other Projects interacts closely with Project 4 for methodological issues. It also shares with the other Projects a strong administrative and scientific infrastructure provided by Cores A (cohort follow-up and data base maintenance), B (confirmation of cancer and cause of death), C (management of the biospecimens) and D (leadership and data analysis). The findings should enhance understanding of the etiology and progression of breast cancer and provide guidance for women and their health care providers in their efforts to reduce suffering and death from this disease.